This invention relates to 6-substituted-2-carbamimidoyl-pen-2-em-3-carboxylic acids (I) and the pharmaceutically acceptable salt, ester and amide derivatives thereof which are useful as antibiotics: ##STR2## wherein R.sup.6 and R.sup.7 are independently selected from the group consisting of: hydrogen; substituted and unsubstituted: alkyl, alkoxyl, alkenyl, and alkynyl, having from 1-10 carbon atoms; halo (especially chloro and fluoro); hydroxyl; carboxyl; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; aryl such as phenyl; aralkyl, aralkenyl, and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heteroalkyl, heterocyclyl and heterocyclylalkyl; wherein the heteroatom or atoms are selected from O, N and S; wherein the substituent or substituents on R.sup.6 and R.sup.7 are independently selected from chloro, fluoro, carboxyl, amino, R.degree.NH, R.degree..sub.2 N (R.degree. is C.sub.1-6 alkyl); bromo, hydroxy, and alkoxyl having 1-6 carbon atoms; additionally R.sup.6 and R.sup.7 may be joined to form, together with the carbon atom to which they are attached, a cyclicalkyl having 3-6 carbon atoms.
R.sup.8 is generically defined to be a "carbamimidoyl", which may be defined by the following structures: ##STR3## wherein A, the cyclic or acylic connecting group, and R.sup.1 and R.sup.2 are defined below. The definition of R.sup.8 also embraces cyclic structures, which may be generically represented, for example, thusly: ##STR4## wherein the dotted lines indicate that the nitrogen atoms of the so-called carbamimidoyl function may participate in the formation of the cyclic structures indicated above. Representative specific embodiments for R.sup.8 (as well as R.sup.6 R.sup.7) follow, but, in the generic sense, the components: R.sup.1, R.sup.2 and A which comprise R.sup.8 are defined, thusly:
A, the cyclic or acyclic connector, is selected from the group consisting of alkyl, alkenyl, and alkynyl having 1-10 carbon atoms which may be interrupted by a hetero atom selected from O, S or N, or by a ring such as phenyl, cycloalkyl, cycloalkenyl, heterocyclyl or heteroaryl wherein such cyclic interruptions comprise 3-6 ring atoms selected from C, O, S and N; cycloalkyl, cycloalkenyl having 3-6 carbon atoms; heterocyclyl; heteroaryl; and phenyl; A also represents a direct, single bond connecting the indicated S and C atoms.
R.sup.1 and R.sup.2 are independently selected from hydrogen and the previously defined values for the group A, such as: alkyl, aryl, cycloalkyl, heteroarlkyl, alkylaryl, alkylarylalkyl, and heterocyclyl and heteroaryl.
R.sup.4 is hydrogen, a removable protecting group, a synthetically useful salt moiety, or a pharmaceutically acceptable salt or ester moiety.
It should be noted that the final products of this invention (I) can exist in either neutral or zwitterionic (internal salt) forms. In the zwitterionic form, the basic function is protonated and positively charged and the carboxyl group is deprotonated and negatively charged. The zwitterionic form is the predominant species under most conditions and is in equilibrium with a minor amount of the uncharged, neutral species. The equilibrium process is conveniently visualized as an internal acid-base neutralization. The neutral and zwitterionic forms are shown below. ##STR5## wherein B is the carbamimidoyl group.
Further, the final products of this invention I wherein R.sup.8 contains a positively charged quaternary nitrogen function such as the "carbamimidinium" can exist as zwitterionic (internal salt) forms or as external salt forms. The preferred form of this product group is the zwitterionic or internal salt form. These forms are shown below: ##STR6## wherein Q represents the quaterized nitrogen group, and wherein X is a pharmaceutically acceptable anion such as those listed in U.S. Pat. No. 4,194,047, issued 3/18/80, which is incorporated herein by reference.
This invention also relates to the carboxyl derivatives of I which are antibiotics and which may be represented by the following generic structure (I): ##STR7## wherein X' is oxygen, sulphur or NR' (R'=H or lower alkyl having 1-6 carbon atoms); and R.sup.3' is, hydrogen, or, inter alia is representatively selected to provide the pharmaceutically acceptable salt, ester, anhydride (R.sup.3' is acyl), and amide moieties known in bicyclic .beta.-lactam antibiotic art; R.sup.3' may also be a readily removable blocking group. The definition of R.sup.3' is given in greater detail below.
This invention also relates to processes for the preparation of such compounds I; pharmaceutical compositions comprising such compounds; and to methods of treatment comprising administering such compounds and compositions when an antibiotic effect is indicated.
There is a continuing need for new antibiotics. For unfortunately, there is no static effectiveness of any given antibiotic because continued wide scale usage selectively gives rise to resistant strains of pathogens. In addition, the known antibiotics suffer from the disadvantage of being effective only against certain types of microorganisms. Accordingly, the search for new antibiotics continues.
Thus, it is an object of the present invention to provide a novel class of antibiotics which are useful in animal and human therapy and in inaminate systems. These antibiotics are active against a broad range of pathogens which representatively include both Gram positive bacteria such as S. aureus, Strep. pyogenes, and B. subtilis, and Gram negative bacteria such as E. coli, Pseudomonas, Proteus morganii, Serratia, and Klebsiella. Further objects of this invention are to provide chemical processes for the preparation of such antibiotics and their nontoxic, pharmaceutically acceptable salts; pharmaceutical compositions comprising such antibiotics; and to provide methods of treatment comprising administering such antibiotics and compositions when an antibiotic effect is indicated.